Regulatory T cells (Tregs) are key mediators of peripheral tolerance that can actively suppress effector T cells, inhibit inflammation and mediate self-tolerance (Kronenberg et al. (2005) Nature 435:598; Sakaguchi et al. (2008) Cell 133:775; Tang et al. (2008) Nat. Immunol. 9:239). Tregs are essential in the maintenance of peripheral tolerance, and roles for B7:CD28 family members during Treg development are emerging (Tang et al. (2003) J. Immunol. 171:3348; Liang et al. (2005) J. Exp. Med. 201:127).
Foxp3 is a transcription factor only expressed in the Treg cell lineage (Hori et al. (2003) Science 299:1057; Fontenot et al. (2003) Nat. Immunol. 4:330; Vignali et al. (2008) Nat. Rev. Immunol. 8:523). Along with contributing a distinct genetic signature to regulatory T cells, Foxp3 conveys regulatory activity to nTregs, iTregs, and, upon ectopic expression, in conventional T cells (Hori et al. (2003) Science 299:1057; Fontenot et al. (2003) Nat. Immunol. 4:330; Gavin et al. (2007) Nature 445:771; Schubert et al. (2001) J. Biol. Chem. 276:37672; (Hill et al. (2007) Immunity 27:786; Fontenot et al. (2005) Immunity 22:329).
The pathway consisting of the receptor programmed death-1 (PD-1) and its ligands, PD-1 ligand-1 (PD-L1) and PD-1 ligand-2 (PD-L2) (B7-DC; CD273) is a recently discovered pathway in the B7:CD28 family that regulates the balance between stimulatory and inhibitory signals needed for effective immunity and the maintenance of self-tolerance (Keir et al. (2007) Curr. Opin. Immunol. 19:309; Keir et al. (2008) Annu. Rev. Immunol. 26:677). PD-1 is upregulated on T cells upon activation and its ligands have distinct expression patterns, with PD-L1 being expressed much more broadly than PD-L2. PD-L1 is constitutively expressed on murine antigen presenting cells (including dendritic cells, macrophages and B cells) and T cells. Human PD-L1 is induced upon activation. PD-L1 is also expressed on a wide variety of hematopoietic and non-hematopoietic cell types, including vascular endothelial cells, pancreatic islet cells, and at sites of immune privilege including the placenta and eye (Keir et al. (2008) Annu Rev Immunol 26:677). In contrast, PD-L2 is inducibly expressed on DCs and macrophages.
PD-1: PD-L interactions regulate peripheral CD4 and CD8 T cell tolerance at multiple checkpoints. PD-1 exerts its effects during the initial phase of activation and expansion of self-reactive T cells, attenuating self-reactive T cell responses during presentation of self-antigen to naïve self-reactive T cells by DCs. For example, loss of PD-1 enhances the responses of naïve self-reactive CD8 T cells upon encounter of dendritic cells (DC) bearing self-antigen (Keir et al. (2007) J. Immunol. 179:5064). In addition, PD-L1 has a role in inhibiting self-reactive effector T cell function. Bone marrow chimera studies have shown that PD-L1 on non-hematopoietic cells mediates tissue tolerance, controlling the intensity of T cell effector responses in non-lymphoid organs and shielding tissues from potentially pathogenic self-reactive T cells and immune-mediated tissue damage (Keir et al. (2006) J. Exp. Med. 203:883).
There is great interest in generating regulatory T cells ex vivo as a therapy for autoimmune diseases and transplant rejection (Roncarolo et al. (2007) Nat. Rev. Immunol. 7:585). However, recent studies indicate that Tregs may have functional plasticity and produce pro-inflammatory cytokines at the site of inflammation (Yang et al. (2008) Immunity; Joetham et al. (2008) J. Immunol. 180:7117). Thus, in order for Treg therapy to be a viable approach, it is desirable to find ways to maintain and enhance the suppressive function of Tregs.